It is now recognized that immune responses play a key role the development and course of atherosclerosis and represent a potential target for therapeutic intervention. Immune therapies such as vaccination and tolerance induction can decrease atherosclerosis in animal models, leading to speculation that this may be a viable preventive measure in humans. However, before immune therapy for human atherosclerosis can be seriously considered, several fundamental questions about atherosclerotic immune responses need to be addressed. Principal among these are the questions of how immune responses to atherosclerosis- associated antigens are initiated, what antigen presenting cells regulate this process, and how specific antigenic epitopes influence T cell response. Here, we will determine how specific dendritic cell (DC) populations contribute to the development of atherosclerosis-associated immune responses and the development of atherosclerosis itself. These populations include vascular DC, which we have shown to be a resident population present in normal arteries in regions that are predisposed to develop atherosclerotic lesions, resident DC populations within lymphoid organs, and inflammatory monocyte-derived DC, which we find to be markedly increased in atherosclerotic mice. We will also determine how specific antigenic epitopes influence atherogenic T cell responses and their influence on the development of atherosclerosis. We anticipate that these studies will lead to much greater understanding of the fundamental mechanisms that regulate the immune responses associated with atherosclerosis and will provide the basis for future therapeutic efforts. PUBLIC HEALTH RELEVANCE: It is now recognized that immune responses play a significant role in regulating the severity of atherosclerosis, suggesting that atherosclerosis may be amenable to immunotherapy. However, our overall understanding of the immunobiology of atherosclerosis remains poor. In this proposal, we address several fundamental questions about how atherosclerotic immune responses are initiated and regulated and how these contribute to the development of atherosclerotic disease.